JP2006507359A5

JP2006507359A5 -

Info

Publication number: JP2006507359A5
Application number: JP2005501508A
Authority: JP
Filing date: 2003-10-14
Publication date: 2006-11-30

Claims

One general formula (I)

(In the above formula,
R ¹ is hydrogen, acyl, alkenyl, cycloalkyl or alkyl, one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N, N-dialkylamino, halogen, cycloalkyl, substituted Are optionally substituted with phenyl or alkoxycarbonyl;
R ² is hydrogen or alkyl;
R ³ and R ⁴ are the same or different and are independent of each other and may be substituted with hydrogen, halogen, hydroxy, mercapto or amino, alkyl or aralkyl;
R ⁵ is hydroxy, halogen, amino, N-alkylamino, N, N-dialkylamino or alkyl substituted with mercapto)
Compound or a pharmaceutically acceptable salt or hydrate or prodrug thereof, comprising an effective amount of those containing optical or geometric isomer or tautomeric form thereof or a mixture, premature heart disease or early heart A medicine for treating cardiovascular diseases .

The above early heart disease or early cardiovascular disease is left ventricular hypertrophy, coronary artery disease, essential hypertension, acute hypertensive emergency, myocardial myopathy, heart failure, exercise test, chronic heart failure, arrhythmia, rhythm abnormality, syncope, artery The medicament according to claim 1, selected from the group consisting of sclerosis, mild chronic heart failure, angina pectoris, cardiac bypass reocclusion, intermittent claudication (obstructive arteriosclerosis), diastolic dysfunction and systolic dysfunction.

The medicament according to claim 1 or 2, wherein the early heart disease or early cardiovascular disease is arrhythmia.

The medicine according to any one of claims 1 to 3, wherein the patient is a non-diabetic patient.

Treatment, medicament according to any one of claims 1 to 4 combined with one or more additional agents.

It said further agents, antiarrhythmics, antidiabetics, antiobesity, lipid regulating agents, medicament according to claim 5 which is selected from the group consisting of antihypertensive agents and osteoporosis drugs.

The medicament according to claim 6, wherein the antiarrhythmic drug is digoxin.

The medicament according to claim 6, wherein the antidiabetic agent is metformin.

The medicament according to claim 6, wherein the antihypertensive agent is an angiotensin converting enzyme inhibitor.

The medicament according to claim 9, wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of captopril, enalapril, fosinoprol, lisnoprol, quinapril, ramipril and spirapril.

The medicament according to claim 6, wherein the blood pressure lowering agent is an angiotensin II receptor antagonist such as losartan.

The medicament according to claim 6, wherein the antihypertensive drug is a non-subtype selective β-adrenergic antagonist.

The medicament according to claim 12, wherein the non-subtype selective β-adrenergic antagonist is selected from the group consisting of propranolol, nadolol, timolol and pindolol.

The medicament according to claim 6, wherein the antihypertensive drug is a selective β ₁ adrenergic antagonist.

The medicament according to claim 14, wherein the selective β ₁ adrenergic antagonist is selected from the group consisting of metoprolol, atenolol, esmolol and acebutolol.

One general formula (I)

(In the above formula,
R ¹ is hydrogen, acyl, alkenyl, cycloalkyl or alkyl, one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N, N-dialkylamino, halogen, cycloalkyl, substituted Are optionally substituted with phenyl or alkoxycarbonyl;
R ² is hydrogen or alkyl;
R ³ and R ⁴ are the same or different and are independent of each other and may be substituted with hydrogen, halogen, hydroxy, mercapto or amino, alkyl or aralkyl;
R ⁵ is hydroxy, halogen, amino, N-alkylamino, N, N-dialkylamino or alkyl substituted with mercapto)
Or a pharmaceutically acceptable salt or hydrate or prodrug thereof, comprising an effective amount of an optical or geometric isomer or tautomeric form or mixture thereof , in connection with heart transplantation A medicament for treatment that increases the viability of the transplanted heart, improves the pump function of the transplanted heart, reduces the frequency of failure of the transplanted heart pump, or reduces the frequency of multiple organ failure .

The medicament according to any one of claims 1 to 16, wherein the compound of formula (I) contains at least two hydroxy groups.

The medicament according to any one of claims 1 to 17, wherein the compound of formula (I) comprises at least three hydroxy groups.

In the compound of formula (I), the two substituents represented by the symbols R ³ and R ⁵ are located on the same side of the face formed by the 5-membered nitrogen-containing ring, and R ⁴ is a 5-membered nitrogen-containing The medicament according to any one of claims 1 to 18, which is located on the opposite side of the surface formed by the ring.

R ¹ is hydrogen or acyl or alkyl optionally substituted by one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N, N-dialkylamino, phenyl or alkoxycarbonyl Item 20. The medicine according to any one of Items 1 to 19.

21. R ¹ is hydrogen or alkyl optionally substituted by one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N, N-dialkylamino, phenyl or alkoxycarbonyl. The medicament according to 1 .

R ¹ is C _1-6 -alkyl optionally substituted by one or more of the following groups: hydroxy, alkoxy, amino, N-alkylamino, N, N-dialkylamino, phenyl or alkoxycarbonyl Item 22. The medicine according to Item 21.

R ¹ is the following groups: hydroxy, alkoxy, amino, N- alkylamino, N, N- dialkylamino, according to claim 22 is phenyl or alkoxy mono- or methyl optionally substituted multiple at the carbonyl Medicine .

R ¹ is substituted with an optionally substituted phenyl group, which may be substituted with one or more of the following groups: halogen, hydroxy, alkoxy, trifluoroalkyl or cyano 24. The medicament according to any one of claims 1 to 23.

The medicament according to any one of claims 1 to 23, wherein R ¹ is hydrogen or alkyl.

R ¹ is _{C 1-6 -} The medicament of claim 25 is alkyl.

The medicament of claim 26 R ¹ is methyl.

The medicament according to claim 21, wherein R ¹ is hydrogen.

R ² is _{C 1-6 -} alkyl medicament according to any one of claims 1 to 28.

The medicament of claim 29 R ² is methyl.

The medicament according to any one of claims 1 to 28 R ² is hydrogen.

The medicament according to any one of claims 1 to 31, wherein R ³ is hydrogen, hydroxy, halogen or amino.

The medicament according to claim 32, wherein R ³ is hydroxy, halogen or amino.

The medicament of claim 33 R ³ is hydroxy or halogen.

The medicament according to claim 34, wherein R ³ is fluoro.

The medicament according to claim 34, wherein R ³ is hydroxy.

R ⁴ is hydrogen, hydroxy, medicament according to any one of claims 1 to 36 halogen or amino.

The medicament of claim 37 R ⁴ is hydroxy, halogen or amino.

The medicament according to claim 38, wherein R ⁴ is hydroxy or halogen.

The medicament of claim 39 R ⁴ is fluoro.

The medicament of claim 39 R ⁴ is hydroxy.

The medicament according to any one of claims 1 to 41, wherein R ⁵ is hydroxyalkyl.

R ⁵ is _{C 1-6 -} The medicament of claim 42 is a hydroxyalkyl.

R ⁵ is hydroxymethyl, medicament according to claim 43, which is a hydroxyethyl or hydroxypropyl.

The medicament of claim 44 R ⁵ is hydroxymethyl.

The medicament according to any one of claims 1 to 41, wherein R ⁵ is benzyloxymethyl.

The compound of general formula (I) is
3,4-dihydroxy-2-hydroxymethylpyrrolidine,
3-4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine,
1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
3,4-dihydroxy-2-hydroxymethyl-1-propylpyrrolidine,
1-butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
3,4-dihydroxy-2-hydroxymethyl-1- (2,2,2-trifluoroethyl) -pyrrolidine,
1-benzyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
3,4-dihydroxy-2-hydroxymethyl-1- (2-hydroxyethyl) pyrrolidine,
3,4-dihydroxy-2-hydroxymethyl-1- (1,3-dihydroxyprop-2-yl) pyrrolidine,
3,4-dihydroxy-2-hydroxymethyl-1- (2,3-dihydroxyprop-1-yl) pyrrolidine,
1- (2-aminoethyl) -3,4-dihydroxy-2-hydroxymethylpyrrolidine,
Or the pharmaceutical according to claim 1 or 16, which is any one of optical isomers thereof.

The compound of general formula (I) is
(2R, 3R, 4R) -3,4 dihydroxy-2-hydroxymethylpyrrolidine,
(2R, 3R, 4R) -3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine,
(2R, 3R, 4R) -1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2R, 3R, 4R) -3,4-dihydroxy-2-hydroxymethyl-1-propylpyrrolidine,
(2R, 3R, 4R) -1-butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2R, 3R, 4R) -3,4-dihydroxy-2-hydroxymethyl-1- (2,2,2-trifluoroethyl) pyrrolidine,
(2R, 3R, 4R) -1-benzyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2R, 3R, 4R) -3,4-dihydroxy-2-hydroxymethyl-1- (2-hydroxyethyl) pyrrolidine,
(2R, 3R, 4R) -3,4-dihydroxy-2-hydroxymethyl-1- (2,3-dihydroxyprop-1-yl) pyrrolidine,
(2R, 3R, 4R) -3,4-dihydroxy-2-hydroxymethyl-1- (1,3-dihydroxyprop-2-yl) pyrrolidine,
(2R, 3R, 4R) -1- (2-aminoethyl) -3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethyl-1-methylpyrrolidine,
(2S, 3S, 4S) -1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethyl-1-propyl-pyrrolidine,
(2S, 3S, 4S) -1-butyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethyl-1- (2,2,2-trifluoroethyl) pyrrolidine,
(2S, 3S, 4S) -1-benzyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethyl-1- (2-hydroxyethyl) pyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethyl-1- (2,3-dihydroxyprop-1-yl) pyrrolidine,
(2S, 3S, 4S) -3,4-dihydroxy-2-hydroxymethyl-1- (1,3-dihydroxyprop-2-yl) -pyrrolidine, or
The medicine according to claim 1 or 16, which is (2S, 3S, 4S) -1- (2-aminoethyl) -3,4-dihydroxy-2-hydroxymethyl-pyrrolidine.

One general formula (II)

(In the above formula,
A is —O—, —S—,>SO,> SO ₂ ,>CO,> CR ¹¹ R ¹² , or> NR ¹³ , where R ¹¹ and R ¹² are independently hydrogen, hydroxy, —SH , Halogen, or C _1-8 -alkyl;
R ¹³ is hydrogen, C _1-8 -alkyl, -carbonyl-C _1-8 -alkyl, or phenyl-C _1-8 -alkyl;
R ⁶ and R ⁷ are each independently hydrogen, CN, —C (O) NR ¹⁴ R ¹⁵ , —COOH, —PO (OH) ₂ , —SO ₂ OH, tetrazole, 1-hydroxy-1,2-diazole 1-hydroxytriazole, 1-hydroxyimidazole, 2-hydroxytriazole, or 1-hydroxytetrazole, wherein R ¹⁴ and R ¹⁵ are independently of each other hydrogen, C _1-8 -alkyl, aryl, phenyl-C _1-8 -alkyl or heteroaryl, each of which is halogen, OH, NH ₂ , NO ₂ , —NH (C _1-8 -alkyl), —N (C _1-8 -alkyl) ₂ , —NHCO Optionally substituted with one or more substituents selected from (C _1-8 -alkyl), C _1-8 -alkoxy, and trifluoromethoxy;
Provided that when R ¹⁴ or R ¹⁵ is hydrogen, the other of R ¹⁴ and R ¹⁵ is —PO (OH) ₂ or —SO ₂ OH;
Or R ⁶ and R ⁷ can together form an anhydride or imide;
R ⁸ and R ⁹ are each independently C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 -alkynyl, or C _3-8 -cycloalkyl, each of which is halogen, hydroxy,- Optionally substituted with SH, —SOR ¹⁶ , —SO ₂ R ¹⁶ , —NR ¹⁶ R ¹⁷ , —NHCOR ¹⁷ , C _1-8 -alkoxy, NO ₂ , trifluoromethoxy, carbamoyl, or CONR ¹⁶ R ¹⁷ ;
Or R ⁸ and R ⁹ are independently of each other hydrogen, halogen, perhalomethyl, C _1-8 -alkoxy, C _1-8 -alkylthio, —SH, —SOR ¹⁶ , —SO ₂ R ¹⁶ , trifluoromethoxy, —SO _{_{2 OH, -PO (OH) 2}} , -COOR 16, -CN, ^{^{^{hydroxy, -OCOR 16, -NR 16 R 17}}} , -NHCOR 17, -COC 1-8 - alkyl, -CONR ¹⁶ R ^17, -CONHSO ₂ R ¹⁷ , —SO ₂ NHR ¹⁷ , NO ₂ , C _1-8 -alkoxycarbonyl, aryl, heteroaryl, C _1-8 -alkylphenyl, or tetrazole, wherein
R ¹⁶ and R ¹⁷ are each independently hydrogen, C _1-8 -alkyl, aryl, phenyl-C _1-8 -alkyl, or heteroaryl, each of halogen, OH, NH ₂ , NO ₂ , — One or more selected from NH (C _1-8 -alkyl), —N (C _1-8 -alkyl) ₂ , —NHCO (C _1-8 -alkyl), C _1-8 -alkoxy, and trifluoromethoxy; Optionally substituted with multiple substituents;
R ¹⁰ is —CO—R ¹⁸ , —CH ₂ —R ¹⁸ , or —CS—R ¹⁸ ;
Where R ¹⁸ is aryl, C _1-8 -alkyl, C _2-8 -alkene, phenyl-C _1-8 -alkyl, heteroaryl, or C _3-8 -cycloalkyl, each of which is halogen, Hydroxy, —SH, —SOR ¹⁹ , —SO ₂ R ¹⁹ , NO ₂ , —NR ¹⁹ R ²⁰ , —NHCOR ²⁰ , C _1-8 -alkyl, C _1-8 -alkoxy, perhalomethoxy, carbamoyl, —CONR ¹⁹ R ²⁰ , perhalomethyl, —OCOR ¹⁹ , —CO—R ¹⁹ , —OR ¹⁹ , C _1-8 -alkylthio, —COOR ¹⁹ , —SO ₂ OH, —SO ₂ CH ₃ , —PO (OH) ₂ , — ^{_{CN, -NHCOR 20, -CONHSO 2 R}} 20, -SO 2 NHR 20, C 1-8 - substituted with an alkoxycarbonyl, and one or more substituents selected from tetrazole It may also be; wherein R ¹⁹ and ^{R 20} independently of one another are hydrogen, _{C 1-8 -} alkyl, aryl, phenyl _{-C 1-8 -} an alkyl, or heteroaryl, each halogen, OH , NH ₂ , NO ₂ , —NH (C _1-8 -alkyl), —N (C _1-8 -alkyl) ₂ , —NHCO (C _1-8 -alkyl), C _1-8 -alkoxy, and tri Optionally substituted with one or more substituents selected from fluoromethoxy)
Compound or a pharmaceutically acceptable salt or hydrate or prodrug thereof, comprising an effective amount of those containing optical or geometric isomer or tautomeric form thereof or a mixture, premature heart disease or early heart A medicine for treating cardiovascular diseases .

The above early heart disease or early cardiovascular disease is left ventricular hypertrophy, coronary artery disease, essential hypertension, acute hypertensive emergency, myocardial myopathy, heart failure, exercise test, chronic heart failure, arrhythmia, rhythm abnormality, syncope, artery 50. The medicament of claim 49, selected from the group consisting of sclerosis, mild chronic heart failure, angina, cardiac bypass re-occlusion, intermittent claudication (obstructive arteriosclerosis), diastolic dysfunction and systolic dysfunction.

51. The medicament according to claim 49 or 50, wherein the early heart disease or early cardiovascular disease is arrhythmia.

52. The medicament according to any one of claims 49 to 51, wherein the patient is a non-diabetic patient.

53. A medicament according to any one of claims 49 to 52, wherein the treatment is combined with one or more further agents.

It said further agents, antiarrhythmics, antidiabetics, antiobesity, lipid regulating agents, medicament according to claim 53 which is selected from the group consisting of antihypertensive agents and osteoporosis drugs.

The medicament of claim 54 antiarrhythmic agent is digoxin.

55. The medicament according to claim 54, wherein the antidiabetic agent is metformin.

55. The medicament according to claim 54, wherein the antihypertensive drug is an angiotensin converting enzyme inhibitor.

58. The medicament according to claim 57, wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of captopril, enalapril, fosinoprol, lisnoprol, quinapril, ramipril and spirapril.

55. The medicament according to claim 54, wherein the antihypertensive drug is an angiotensin II receptor antagonist such as losartan.

55. The medicament according to claim 54, wherein the antihypertensive drug is a non-subtype selective beta adrenergic antagonist.

61. The medicament of claim 60, wherein the non-subtype selective beta adrenergic antagonist is selected from the group consisting of propranolol, nadolol, timolol and pindolol.

55. The medicament of claim 54, wherein the antihypertensive drug is a selective β ₁ adrenergic antagonist.

63. The medicament of claim 62, wherein the selective β ₁ adrenergic antagonist is selected from the group consisting of metoprolol, atenolol, esmolol and acebutolol.

One general formula (II)

(In the above formula,
A is —O—, —S—,>SO,> SO ₂ ,>CO,> CR ¹¹ R ¹² , or> NR ¹³ , where R ¹¹ and R ¹² are independently hydrogen, hydroxy, —SH , Halogen, or C _1-8 -alkyl;
R ¹³ is hydrogen, C _1-8 -alkyl, -carbonyl-C _1-8 -alkyl, or phenyl-C _1-8 -alkyl;
R ⁶ and R ⁷ are each independently hydrogen, CN, —C (O) NR ¹⁴ R ¹⁵ , —COOH, —PO (OH) ₂ , —SO ₂ OH, tetrazole, 1-hydroxy-1,2-diazole 1-hydroxytriazole, 1-hydroxyimidazole, 2-hydroxytriazole, or 1-hydroxytetrazole, wherein R ¹⁴ and R ¹⁵ are independently of each other hydrogen, C _1-8 -alkyl, aryl, phenyl-C _1-8 -alkyl or heteroaryl, each of which is halogen, OH, NH ₂ , NO ₂ , —NH (C _1-8 -alkyl), —N (C _1-8 -alkyl) ₂ , —NHCO Optionally substituted with one or more substituents selected from (C _1-8 -alkyl), C _1-8 -alkoxy, and trifluoromethoxy;
Provided that when R ¹⁴ or R ¹⁵ is hydrogen, the other of R ¹⁴ and R ¹⁵ is —PO (OH) ₂ or —SO ₂ OH;
Or R ⁶ and R ⁷ can together form an anhydride or imide;
R ⁸ and R ⁹ are each independently C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 -alkynyl, or C _3-8 -cycloalkyl, each of which is halogen, hydroxy,- May be substituted with SH, -SOR ¹⁶ , -SO ₂ R ¹⁶ , -NR ¹⁶ R ¹⁷ , -NHCOR ¹⁷ , C _1-8 -alkoxy, NO ₂ , trifluoromethoxy, carbamoyl, or -CONR ¹⁶ R ¹⁷ Often;
Or R ⁸ and R ⁹ are independently of each other hydrogen, halogen, perhalomethyl, C _1-8 -alkoxy, C _1-8 -alkylthio, —SH, —SOR ¹⁶ , —SO ₂ R ¹⁶ , trifluoromethoxy, —SO _{_{2 OH, -PO (OH) 2}} , -COOR 16, -CN, ^{^{^{hydroxy, -OCOR 16, -NR 16 R 17}}} , -NHCOR 17, -COC 1-8 - alkyl, -CONR ¹⁶ R ^17, -CONHSO ₂ R ¹⁷ , —SO ₂ NHR ¹⁷ , NO ₂ , C _1-8 -alkoxycarbonyl, aryl, heteroaryl, C _1-8 -alkylphenyl, or tetrazole, wherein
R ¹⁶ and R ¹⁷ are each independently hydrogen, C _1-8 -alkyl, aryl, phenyl-C _1-8 -alkyl, or heteroaryl, each of halogen, OH, NH ₂ , NO ₂ , — One or more selected from NH (C _1-8 -alkyl), —N (C _1-8 -alkyl) ₂ , —NHCO (C _1-8 -alkyl), C _1-8 -alkoxy, and trifluoromethoxy; Optionally substituted with multiple substituents;
R ¹⁰ is —CO—R ¹⁸ , —CH ₂ —R ¹⁸ , or —CS—R ¹⁸ ;
Where R ¹⁸ is aryl, C _1-8 -alkyl, C _2-8 -alkene, phenyl-C _1-8 -alkyl, heteroaryl, or C _3-8 -cycloalkyl, each of which is halogen, Hydroxy, —SH, —SOR ¹⁹ , —SO ₂ R ¹⁹ , NO ₂ , —NR ¹⁹ R ²⁰ , —NHCOR ²⁰ , C _1-8 -alkyl, C _1-8 -alkoxy, perhalomethoxy, carbamoyl, —CONR ¹⁹ R ²⁰ , perhalomethyl, —OCOR ¹⁹ , —CO—R ¹⁹ , —OR ¹⁹ , C _1-8 -alkylthio, —COOR ¹⁹ , —SO ₂ OH, —SO ₂ CH ₃ , —PO (OH) ₂ , — ^{_{CN, -NHCOR 20, -CONHSO 2 R}} 20, -SO 2 NHR 20, C 1-8 - substituted with an alkoxycarbonyl, and one or more substituents selected from tetrazole It may also be; wherein R ¹⁹ and ^{R 20} independently of one another are hydrogen, _{C 1-8 -} alkyl, aryl, phenyl _{-C 1-8 -} an alkyl, or heteroaryl, each halogen, OH , NH ₂ , NO ₂ , —NH (C _1-8 -alkyl), —N (C _1-8 -alkyl) ₂ , —NHCO (C _1-8 -alkyl), C _1-8 -alkoxy, and tri Optionally substituted with one or more substituents selected from fluoromethoxy)
Or an pharmaceutically acceptable salt or hydrate or prodrug thereof, comprising an effective amount of an optical or geometric isomer or tautomeric form or mixture thereof , in connection with heart transplantation A medicament for treatment that increases the viability of the transplanted heart, improves the pump function of the transplanted heart, reduces the frequency of failure of the transplanted heart pump, or reduces the frequency of multiple organ failure .

The medicament according to any one of claims 49 to 64, wherein A is -O- or -S-.

Or R ⁶ and ^{R 7} are both -COOH or CN, or medicament according to any one of claims 49 to 65 wherein R ⁶ and ^{R 7} form an imide jointly.

The medicament according to any one of claims 49 to 66 R ⁸ is hydrogen.

68. The medicament according to any one of claims 49 to 67, wherein R ¹⁶ and R ¹⁷ are independently of each other hydrogen or C _1-8 -alkyl.

R ¹⁰ is ^{-CO-R 18,} wherein medicament according to any one of ^{R 18} is the preceding claims 49 which is as defined above 68.

R ¹⁸ is halogen, hydroxy, —SH, —SOR ¹⁹ , —SO ₂ R ¹⁹ , NO ₂ , —NR ¹⁹ R ²⁰ , —NHCOR ²⁰ , C _1-8 -alkyl, C _1-8 -alkoxy, perhalo Methoxy, carbamoyl, —CONR ¹⁹ R ²⁰ , perhalomethyl, —OCOR ¹⁹ , —CO—R ¹⁹ , —OR ¹⁹ , C _1-8 -alkylthio, —COOR ¹⁹ , —SO ₂ OH, —SO ₂ CH ₃ , —PO (OH) ₂ , —CN, —NHCOR ²⁰ , —CONHSO ₂ R ²⁰ , —SO ₂ NHR ²⁰ , C _1-8 -alkoxycarbonyl, and substituted with one or more substituents selected from tetrazole Good aryl, where
The medicament of claim 69 R ¹⁹ and ^{R 20} are as defined above.

R ¹⁸ is ^{_{halogen, -COOR 12, NO 2, -SO}} 2 CH 3, CN, C 1-8 - alkyl, perhalomethyl, _{C 1-8 -} alkoxy, perhalo methoxy, _{C 1-8 -} alkylthio, -CO An aryl optionally substituted with one or more substituents selected from —R ¹⁹ , —NR ¹⁹ R ²⁰ , —NH—CO—R ²⁰ , and —OR ¹⁹ , wherein
The medicament of claim 70 R ¹⁹ and ^{R 20} are as defined above.

R ¹⁹ and ^{R 20} are hydrogen or independently of one another _{C 1-8 -} The medicament of claim 71 is alkyl.

A compound of the general formula (IIa) for the preparation of a pharmaceutical composition for treating early heart disease or early cardiovascular disease in a patient in need of treatment

(In the above formula,
A is —O— or —S—;
R ⁶ and R ⁷ are both —COOH or CN, or R ⁶ and R ⁷ together form an imide;
R ⁹ is C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 -alkynyl, or C _3-8 -cycloalkyl, each of which is halogen, hydroxy, —SH, —SOR ¹⁶ , — _{^{^{SO 2 R 16, -NR 16 R}}} 17, -NHCOR 17, C 1-8 - alkoxy, NO _2, trifluoromethoxy, carbamoyl, or may be substituted by ^CONR 16 ^{R 17;} or ^{R 9} is hydrogen, Halogen, perhalomethyl, C _1-8 -alkoxy, C _1-8 -alkylthio, —SH, —SOR ¹⁶ , —SO ₂ R ¹⁶ , trifluoromethoxy, —SO ₂ OH, —PO (OH) ₂ , —COOR ¹⁶ , -CN, ^{^{^{hydroxy, -OCOR 16, -NR 16 R 17}}} , -NHCOR 17, -COC 1-8 - ^{^{_{alkyl, -CONR 16 R 17, -CONHSO 2}}} R 1 _{^{_{, -SO 2 NHR 17, NO 2}}} , C 1-8 - alkoxycarbonyl, aryl, heteroaryl, _{C 1-8 -} alkyl phenyl, or tetrazole, wherein
R ¹⁶ and R ¹⁷ are independently of each other hydrogen or C _1-8 -alkyl; R ¹⁸ is halogen, —COOR ¹⁹ , NO ₂ , —SO ₂ CH ₃ , CN, C _1-8 -alkyl, perhalomethyl, One or more selected from C _1-8 -alkoxy, perhalomethoxy, C _1-8 -alkylthio, —CO—R ¹⁹ , —NR ¹⁹ R ²⁰ , —NH—CO—R ²⁰ , and —OR ¹⁹ Aryl optionally substituted with substituents, wherein R ¹⁹ and R ²⁰ are independently of each other hydrogen or C _1-8 -alkyl)
A compound according to any one of claims 49 to 72, comprising an optical or geometric isomer or a tautomeric form or a mixture thereof, or a pharmaceutically acceptable salt or hydrate or prodrug thereof. Medicine .

74. The medicament according to claim 73, wherein A is -O-.

R ⁹ is C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 -alkynyl, or C _3-8 -cycloalkyl, which is halogen, hydroxy, —SH, —SOR ¹⁶ , —SO Optionally substituted with ₂ R ¹⁶ , —NR ¹⁶ R ¹⁷ , —NHCOR ¹⁷ , C _1-8 -alkoxy, NO ₂ , trifluoromethoxy, carbamoyl, or CONR ¹⁶ R ¹⁷ ; or R ⁹ is hydrogen, halogen , Perhalomethyl, C _1-8 -alkoxy, C _1-8 -alkylthio, —SH, —SOR ¹⁶ , —SO ₂ R ¹⁶ , trifluoromethoxy, —SO ₂ OH, —PO (OH) ₂ , —COOR ¹⁶ , -CN, ^{^{^{hydroxy, -OCOR 16, -NR 16 R 17}}} , -NHCOR 17, -COC 1-8 - ^{^{_{alkyl, -CONR 16 R 17, -CONHSO 2}}} R 17, -S _{^{_{_{2 NHR 17, NO 2, C}}}} 1-8 - alkoxycarbonyl, _{C 1-8 -} alkyl phenyl, or tetrazole, wherein
R ¹⁶ and ^{R 17} are hydrogen or _{C 1-8} independently of one another _- alkyl, medicament according to claim 73 or 74.

R ⁹ is C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 -alkynyl, or C _3-8 -cycloalkyl, halogen, hydroxy, —SH, —SOH, —SO ₂ Optionally substituted with H, —NH ₂ , —NHCOH, C _1-8 -alkoxy, NO ₂ , trifluoromethoxy, carbamoyl, or CONH ₂ ; or R ⁹ is hydrogen, halogen, perhalomethyl, C _1-8. - alkoxy, _{C 1-8 -} _{alkylthio, -SH, -SOH, -SO 2 H} , _{trifluoromethoxy, -SO 2 OH, -PO (OH} ) 2, -COOH, -CN, hydroxy, -OCOH, -NH ₂ , —NHCOH, —COC _1-8 -alkyl, —CONH ₂ , —CONHSO ₂ H, —SO ₂ NH ₂ , NO ₂ , C _1-8 -alkoxycarbonyl, aryl, heteroaryl, C _{1 75.} The medicament according to claim 73 or 74, which is _-8- alkylphenyl or tetrazole.

R ⁹ is C _1-8 -alkyl, C _2-8 -alkenyl, C _2-8 -alkynyl, or C _3-8 -cycloalkyl, halogen, hydroxy, —SH, —SOH, —SO ₂ _{_{H, -NH 2, -NHCOH, C}} 1-8 - alkoxy, NO _2, trifluoromethoxy, carbamoyl, or may be substituted by CONH _2; or ^{R 9} is hydrogen, halogen, _{perhalomethyl, C 1-8} - alkoxy, _{C 1-8 -} _{alkylthio, -SH, -SOH, -SO 2 H} , _{trifluoromethoxy, -SO 2 OH, -PO (OH} ) 2, -COOH, -CN, hydroxy, -OCOH, -NH _{_{2, -NHCOH, -CO-C 1-8}} - _{_{alkyl, -CONH 2, -CONHSO 2 H,}} -SO 2 NH 2, NO 2, C 1-8 - alkoxycarbonyl, _{C 1-8 -} alkyl phenyl, and 77. The medicament according to claim 75 or 76, which is tetrazole.

The medicament according to any one of claims 73 to 77 R ⁹ is hydrogen.

The compound is represented by the general formula (IIb)

(Wherein R ⁶ , R ⁷ and R ¹⁸ are as defined in claim 73)
74. The medicament according to claim 73, wherein

The medicament according to any one of claims 73 to 79 R ⁶ and ^{R 7} are both -COOH.

The compound is represented by the general formula (IIc)

(Wherein R ¹⁸ is as defined in claim 73)
74. The medicament according to claim 73, wherein

R ¹⁸ is ^{_{halogen, COOR 19, NO 2, -SO}} 2 CH 3, CN, C 1-8 - alkyl, perhalomethyl, _{C 1-8 -} alkoxy, perhalo methoxy, _{C 1-8 -} alkylthio, -CO- R ¹⁹ , —NR ¹⁹ N ²⁰ , —NH—CO—R ²⁰ , and —OR ¹⁹ are phenyl optionally substituted with one or more substituents;
R ¹⁹ and ^{R 20} are hydrogen or independently of one another _{C 1-8 -} alkyl medicament according to any one of claims 73 to 81.

R ¹⁸ is substituted, medicament according to any one of to one of the substituents claims 73 is NO ₂ 82.

R ¹⁸ is substituted, methyl one of the substituents, tert- butyl, isopropyl, pentyl, or medicament according to any one of claims 73 to 83 heptyl.

R ¹⁸ is substituted, medicament according to any one of to one of the substituents claims 73 trifluoromethyl 84.

R ¹⁸ is substituted, medicament according to any one of to one of the substituents claims 73 methoxy or ethoxy 85.

R ¹⁸ is substituted, medicament according to any one of to one of the substituents claims 73 trifluoromethoxy 86.

R ¹⁸ is substituted, medicament according to any one of to one of the substituents claims 73 methylthio 86.

The compound of general formula (II) is
4- [2- (3-dimethylaminobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-dimethylaminobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-iodobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-iodobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (2-fluoro-5-trifluoromethylbenzoylamino) phenoxy] phthalic acid,
4- [2- (2-Fluoro-5-trifluoromethylbenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (2-fluorobenzoylamino) phenoxy] phthalic acid,
4- [2- (2-fluorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-acetylbenzoylamino) phenoxy] phthalic acid,
4- [2- (3-acetylbenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-bromobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-bromobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-chlorobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-chlorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (2,3-difluorobenzoylamino) phenoxy] phthalic acid,
4- [2- (2,3-difluorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (2,4-difluorobenzoylamino) phenoxy] phthalic acid,
4- [2- (2,4-difluorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (2,5-difluorobenzoylamino) phenoxy] phthalic acid,
4- [2- (2,5-difluorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (4-fluorobenzoylamino) phenoxy] phthalic acid,
4- [2- (4-fluorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- (2-benzoylaminophenoxy) phthalic acid,
4- (2-benzoylaminophenoxy) phthalic acid dimethyl ester,
4- [2- (3-methylbenzoylamino) phenoxy] phthalic acid,
4- [2- (3-methylbenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-cyanobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-cyanobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-amino-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-amino-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
N- [2- (1,3-dioxo-2,3-dihydro-1H-isoindol-5-yloxy) phenyl] -3-nitrobenzamide,
4- [2- (3-aminobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-aminobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-nitrobenzoylamino) phenylsulfenyl] phthalic acid,
4- [2- (3-nitrobenzoylamino) phenylsulfenyl] phthalic acid dimethyl ester,
4- [2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4- (4-Iodobenzoylamino) -2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4- (4-Iodobenzoylamino) -2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-methoxycarbonyl-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-methoxycarbonyl-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-acetylamino-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-acetylamino-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [5-Fluoro-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [5-Fluoro-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-Bromo-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-Bromo-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-benzoylamino-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-benzoylamino-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-cyano-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-cyano-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-methyl-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-Methyl-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [4-Fluoro-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [4-Fluoro-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [5-methyl-2- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [5-Methyl-2- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-nitrobenzoylamino) -4-trifluoromethylphenoxy] phthalic acid,
4- [2- (3-nitrobenzoylamino) -4-trifluoromethylphenoxy] phthalic acid dimethyl ester,
4- [2,4-bis- (3-nitrobenzoylamino) phenoxy] phthalic acid,
4- [2,4-bis- (3-nitrobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-fluorobenzoylamino) phenoxy] phthalic acid,
4- [2- (3-Fluorobenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-trifluoromethylbenzoylamino) phenoxy] phthalic acid,
4- [2- (3-trifluoromethylbenzoylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-nitrobenzylamino) phenoxy] phthalic acid,
4- [2- (3-nitrobenzylamino) phenoxy] phthalic acid dimethyl ester,
4- [2- (3-trifluoromethoxybenzoylamino) phenoxy] phthalic acid,
4- [2- (3-trifluoromethoxybenzoylamino) phenoxy] phthalic acid dimethyl ester,
65. The medicament according to claim 49 or 64, which is 4- [2- (3-methoxybenzoylamino) phenoxy] phthalic acid or 4- [2- (3-methoxybenzoylamino) phenoxy] phthalic acid dimethyl ester.

One general formula (III)

(In the above formula,
R ²¹ is hydrogen, monosaccharide moiety or alkyl, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl and alkylphenyl Which may be substituted with one or more groups selected from
Or R ²¹ in combination with the adjacent nitrogen atom of the piperidine nucleus, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl And a quaternary ammonium base ion residue containing two alkyl groups optionally substituted with one or more groups selected from alkylphenyl;
R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, acylamino, N, N-dialkylamino, N, N, N-trialkylammonium Ion, nitro, formyl, carboxy, benzyloxy, mercapto, alkylthio, alkenyl, phenyl or alkylphenyl;
R ²⁶ is one or more selected from alkyl, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl and alkylphenyl. Phenyl or methyl optionally substituted by the group
Provided that the compound contains at least two free or protected hydroxyl groups)
Compound or a pharmaceutically acceptable salt or hydrate or prodrug thereof, comprising an effective amount of those containing optical or geometric isomer or tautomeric form thereof or a mixture, premature heart disease or early heart A medicine for treating cardiovascular diseases .

The above early heart disease or early cardiovascular disease is left ventricular hypertrophy, coronary artery disease, essential hypertension, acute hypertensive emergency, myocardial myopathy, heart failure, exercise test, chronic heart failure, arrhythmia, rhythm abnormality, syncope, artery 92. The medicament of claim 90, selected from the group consisting of sclerosis, mild chronic heart failure, angina, cardiac bypass reocclusion, intermittent claudication (obstructive arteriosclerosis), diastolic dysfunction and systolic dysfunction.

92. The medicament according to claim 90 or 91, wherein the early heart disease or early cardiovascular disease is arrhythmia.

93. The medicament according to any one of claims 90 to 92, wherein the patient is a non-diabetic patient.

Treatment, medicament according to any one of claims 90 to 93 combined with one or more additional agents.

It said further agents, antiarrhythmics, antidiabetics, antiobesity, lipid regulating agents, medicament according to claim 94 which is selected from the group consisting of antihypertensive agents and osteoporosis drugs.

The medicament of claim 95 antiarrhythmic agent is digoxin.

96. The medicament according to claim 95, wherein the antidiabetic agent is metformin.

96. The medicament according to claim 95, wherein the blood pressure lowering agent is an angiotensin converting enzyme inhibitor.

99. The medicament of claim 98, wherein the angiotensin converting enzyme inhibitor is selected from the group consisting of captopril, enalapril, fosinoprol, lisnoprol, quinapril, ramipril and spirapril.

96. The medicament according to claim 95, wherein the antihypertensive drug is an angiotensin II receptor antagonist such as losartan.

96. The medicament according to claim 95, wherein the antihypertensive drug is a non-subtype selective β-adrenergic antagonist.

102. The medicament of claim 101, wherein the non-subtype selective beta adrenergic antagonist is selected from the group consisting of propranolol, nadolol, timolol and pindolol.

96. The medicament according to claim 95, wherein the antihypertensive drug is a selective β ₁ adrenergic antagonist.

104. The medicament of claim 103, wherein the selective [beta] _l adrenergic antagonist is selected from the group consisting of metoprolol, atenolol, esmolol and acebutolol.

One general formula (III)

(In the above formula,
R ²¹ is hydrogen, monosaccharide moiety or alkyl, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl and alkylphenyl Which may be substituted with one or more groups selected from
Or R ²¹ in combination with the adjacent nitrogen atom of the piperidine nucleus, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl And a quaternary ammonium base ion residue containing two alkyl groups optionally substituted with one or more groups selected from alkylphenyl;
R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, acylamino, N, N-dialkylamino, N, N, N-trialkylammonium Ion, nitro, formyl, carboxy, benzyloxy, mercapto, alkylthio, alkenyl, phenyl or alkylphenyl;
R ²⁶ is one or more selected from alkyl, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl and alkylphenyl. Phenyl or methyl optionally substituted by the group
Provided that the compound contains at least two free or protected hydroxyl groups)
Or a pharmaceutically acceptable salt or hydrate or prodrug thereof, comprising an effective amount of an optical or geometric isomer or tautomeric form or mixture thereof , in connection with heart transplantation A medicament for treatment that increases the viability of the transplanted heart, improves the pump function of the transplanted heart, reduces the frequency of failure of the transplanted heart pump, or reduces the frequency of multiple organ failure .

The compound is 3,4-dihydroxy-5-methylpiperidine, (3R, 4R, 5R) -3,4-dihydroxy-5-hydroxymethylpiperidine, and 3-benzyloxy-4-hydroxy-5-hydroxymethylpiperidine; 106. The medicament according to any one of claims 90 to 105, which is different from the salt thereof and a salt thereof.

R ²¹ is hydrogen, a monosaccharide moiety or C _1-6 -alkyl, hydroxy, C _1-6 -hydroxyalkyl, halogen, amino, C _1-6 -alkylamino, di-C _1-6 -alkyl-amino , Tri-C _1-6 -alkyl-ammonium ions, nitro, formyl, carboxy, C _1-6 -carboxyalkyl, C _1-6 -alkylthio, C _2-6 -alkenyl, phenyl and C _1-6 -alkylphenyl 107. The pharmaceutical according to any one of claims 90 to 106, which may be substituted with one or more groups selected from the group consisting of:

R ²¹ is hydrogen, medicament according to any one of claims 90 to 106 is a monosaccharide moiety or alkyl.

R ²¹ is hydrogen, a monosaccharide moiety or _{C 1-6 -} The medicament of claim 107 or 108 is alkyl.

The medicament of claim 109 R ²¹ is hydrogen, monosaccharide moiety or methyl.

R ²¹ in combination with the adjacent nitrogen atom of the piperidine nucleus is hydroxy, C _1-6 -hydroxyalkyl, halogen, amino, C _1-6 -alkylamino, di-C _1-6 -alkyl-amino, tri- Selected from C _1-6 -alkyl-ammonium ions, nitro, formyl, carboxy, C _1-6 -carboxyalkyl, C _1-6 -alkylthio, C _2-6 -alkenyl, phenyl and C _{1-6 -alkylphenyl} 107. The medicament according to any one of claims 90 to 106, which is a quaternary ammonium base ion residue containing two C _1-6 -alkyl groups _optionally substituted with one or more groups.

R ²¹ is, together with the adjacent nitrogen atom of the piperidine nucleus, medicament according to any one of claims 90 to 106 is a dialkylammonium ion.

R ²¹ is, together with the adjacent nitrogen atom, di _{-C 1-6 -} alkyl - The medicament of claim 111 or 112 is an ammonium ion.

R ²¹ is, together with the adjacent nitrogen atom, A medicament according to claim 113 which is dimethyl ammonium ion.

R ²² , R ²³ , R ²⁴ and R ²⁵ are independently of each other hydrogen, hydroxy, C _1-6 -hydroxyalkyl, halogen, amino, C _1-6 -alkylamino, C _1-6 -acylamino, N , N-di-C _1-6 -alkyl-amino, N, N, N-tri-C _1-6 -alkyl-ammonium ion, nitro, formyl, carboxy, benzyloxy, mercapto, C _1-6 -alkylthio, _115. The medicament according to any one of claims 90 to 114, which is _C2-6- alkenyl, phenyl or C1-6-alkylphenyl.

The medicament according to any one of claims 90 to 115 R ²² is hydrogen.

R ²³ is hydroxy, medicament according to any one of claims 90 to 116 is a halogen or benzyloxy.

R ²³ is hydroxy, fluoro, medicament according to claim 117 is chloro or benzyloxy.

The medicament according to any one of claims 90 to 118 R ²⁴ is hydroxy or halogen.

R ²⁴ is hydroxy, fluoro, or medicament according to claim 119 is chloro.

The medicament according to any one of claims 90 to 120 R ²⁵ is hydrogen.

R ²⁶ is one or more selected from alkyl, hydroxy, hydroxyalkyl, halogen, amino, alkylamino, dialkylamino, trialkylammonium ion, nitro, formyl, carboxy, carboxyalkyl, alkylthio, alkenyl, phenyl and alkylphenyl. 122. The medicament according to any one of claims 90 to 121, which is methyl optionally substituted by

R ²⁶ represents C _1-6 -alkyl, hydroxy, C _1-6 -hydroxyalkyl, halogen, amino, C _1-6 -alkylamino, di-C _1-6 -alkyl-amino, tri-C _1-6. One or more selected from -alkyl-ammonium ions, nitro, formyl, carboxy, C _1-6 -carboxyalkyl, C _1-6 -alkylthio, C _2-6 -alkenyl, phenyl and C _{1-6 -alkylphenyl} 122. The pharmaceutical according to any one of claims 90 to 121, which is phenyl or methyl optionally substituted by

R ²⁶ represents C _1-6 -alkyl, hydroxy, C _1-6 -hydroxyalkyl, halogen, amino, C _1-6 -alkylamino, di-C _1-6 -alkyl-amino, tri-C _1-6. One or more selected from -alkyl-ammonium, nitro, formyl, carboxy, C _1-6 -carboxyalkyl, C _1-6 -alkylthio, C _2-6 -alkenyl, phenyl and C _{1-6 -alkylphenyl} 124. The pharmaceutical according to claim 122 or 123, which is methyl optionally substituted with a group.

R ²⁶ is hydroxymethyl, hydroxyethyl, ethyl, propyl, isopropyl, fluoromethyl, The medicament of claim 123 chloromethyl or phenyl.

126. The medicament according to any one of claims 90 to 125, wherein the compound comprises at least two free hydroxyl groups.

126. A medicament according to any one of claims 90 to 125, wherein the compound comprises at least three free or protected hydroxyl groups.

128. A medicament according to claim 126 or 127, wherein the compound comprises at least three free hydroxyl groups.

129. A medicament according to any one of claims 90 to 128, wherein free or protected hydroxyl groups are the substituents R ²³ , R ²⁴ and R ²⁶ or are present in said substituents.

The compound of general formula (III) is
(3R, 4R, 5R) -3,4-dihydroxy-5-hydroxymethylpiperidine,
3,4-dihydroxy-5-hydroxymethylpiperidine,
3-benzyloxy-4-hydroxy-5-hydroxymethylpiperidine,
3,4-dihydroxy-5-hydroxymethylpiperidine N- (7- (methyl 6,7-dideoxy-D- gluco -heptopyranoside)),
3,4-dihydroxy-5-methylpiperidine,
3,4-dihydroxy-5-ethylpiperidine,
3,4-dihydroxy-5-propylpiperidine,
3,4-dihydroxy-5-isopropylpiperidine,
3,4-dihydroxy-5-phenylpiperidine,
3,4-dihydroxy-5-hydroxyethylpiperidine,
3,4-dihydroxy-5-fluoromethylpiperidine,
3,4-dihydroxy-5-chloromethylpiperidine,
3-hydroxy-5-hydroxymethylpiperidine,
3-hydroxy-4-fluoro-5-hydroxymethylpiperidine,
3-hydroxy-4-chloro-5-hydroxymethylpiperidine,
3-fluoro-4-hydroxy-5-hydroxymethylpiperidine,
3-chloro-4-hydroxy-5-hydroxymethylpiperidine,
4-hydroxy-5-hydroxymethylpiperidine,
106. The medicament according to claim 90 or 105, which is N-methyl-3,4-dihydroxy-5-hydroxymethylpiperidine or N, N-dimethyl-3,4-dihydroxy-5-hydroxymethylpiperidinium chloride.